Embryonic NIPP1 depletion in keratinocytes triggers a cell-cycle arrest and premature senescence in adult mice.

NIPP1 is a ubiquitously expressed regulatory subunit of protein phosphatase-1. Its embryonic deletion in keratinocytes causes chronic sterile skin inflammation, epidermal hyperproliferation and resistance to mutagens in adult mice. To explore the primary effects of NIPP1 deletion, we first examined hair-cycle progression of NIPP1 skin knockouts (SKOs). The entry of the 1st hair cycle in the SKOs was delayed due to prolonged quiescence of hair-follicle stem cells (HFSCs). In contrast, the entry of the 2nd hair cycle in the SKOs was advanced as a result of precocious activation of HFSCs. The epidermis of SKOs progressively accumulated senescent cells and this cell-fate switch was accelerated by DNA damage. Primary keratinocytes from SKO neonates and human NIPP1-depleted HaCaT keratinocytes failed to proliferate and showed an increase in the expression of cell-cycle inhibitors (p21, p16/Ink4a and/or p19/Arf) and senescence-associated-secretory-phenotype (SASP) factors as well as in DNA damage (γH2AX and 53bp1). Our data demonstrate that the primary effect of NIPP1 deletion in keratinocytes is a cell-cycle arrest and premature senescence that gradually progresses to chronic senescence and likely contributes to the decreased sensitivity of SKOs to mutagens.